REGION-SPECIFIC CHANGES OF GABA(A) RECEPTORS BY TOLERANCE TO AND DEPENDENCE UPON PENTOBARBITAL

An experimental model for inducing tolerance to and dependence upon pe ntobarbital was characterized. Rats were infused with pentobarbital, 3 00 mug/10 mul per h i.c.v. for 6 or 7 days, through pre-implanted cann ulas by osmotic minipumps. Measurement of brain and serum levels showe d that pentobarbital remained mainly inside of the brain. Measurements of sleeping time and susceptibility to convulsant-induced seizures in dicated a substantial degree of tolerance and dependence (24 h after t ermination of infusion). Results of GABA(A) receptor binding assays sh owed marked regional variations. While [S-35]t-butylbicyclophosphoroth ionate (TBPS) binding sites were increased in frontal cortices and str iata of pentobarbital-dependent animals, K(D) was increased in striata of tolerant animals. Dependence upon pentobarbital was correlated wit h increased [H-3]flunitrazepam binding sites in all three regions exam ined. Both high and low affinity [H-3]muscimol binding sites were incr eased in dependent animals, but low affinity sites were decreased in f rontal cortices of tolerant animals. K(D)s of [H-3]muscimol high affin ity sites were increased in cerebellum after animals developed depende nce upon pentobarbital. K(D)s of [H-3]muscimol low affinity sites were decreased in striata of pentobarbital tolerant animals. These finding s further support the hypothesis that GABA(A) receptors in discrete ar eas of the brain have different subunit compositions and are regulated differentially by pharmacological modulators.